BACKGROUND & AIMS Prolactin (PRL) is a multifunctional polypeptide with effects on metabolism, however, little is known about its effect on hepatic steatosis and lipid metabolism. Herein, we aimed to assess the role of PRL in the development of non-alcoholic fatty liver disease (NAFLD). METHODS The serum PRL levels of 456 patients with NAFLD, 403 controls without NAFLD diagnosed by ultrasound, and 85 individuals with liver histology obtained during metabolic surgery (44 female and 30 male patients with NAFLD and 11 age-matched non-NAFLD female individuals) were evaluated. The expression of the gene encoding the prolactin receptor (PRLR) and signalling molecules involved in hepatic lipid metabolism were evaluated in human liver and HepG2 cells. The effects of overexpression of PRLR or fatty acid translocase (FAT)/CD36 or knockdown of PRLR on hepatic lipid metabolism were tested in free fatty acid (FFA)-treated HepG2 cells. RESULTS Circulating PRL levels were lower in individuals with ultrasound-diagnosed NAFLD (men: 7.9 [range, 5.9-10.3] µg/L; women: 8.7 [range, 6.1-12.4] µg/L) than those with non-NAFLD (men: 9.1 [range, 6.8-13.0] µg/L, p = 0.002; women: 11.6 [range, 8.2-16.1] µg/L, p <0.001). PRL levels in patients with biopsy-proven severe hepatic steatosis were lower compared with those with mild-to-moderate hepatic steatosis in both men (8.3 [range, 5.4-9.5] µg/L vs. 9.7 [range, 7.1-12.3] µg/L, p = 0.031) and women (8.5 [range, 4.2-10.6] µg/L vs. 9.8 [range, 8.2-15.7] µg/L, p = 0.027). Furthermore, hepatic PRLR gene expression was significantly reduced in patients with NAFLD and negatively correlated with CD36 gene expression. In FFA-induced HepG2 cells, PRL treatment or PRLR overexpression significantly reduced the expression of CD36 and lipid content, effects that were abrogated after silencing of PRLR. Furthermore, overexpression of CD36 significantly reduced the PRL-mediated improvement in lipid content. CONCLUSIONS Our results reveal a novel association between the central nervous system and the liver, whereby PRL/PRLR improved hepatic lipid accumulation via the CD36 pathway. LAY SUMMARY Our clinical study suggests a negative association between prolactin (PRL)/prolactin receptor (PRLR) and the presence of non-alcoholic fatty liver disease (NAFLD). Using cell experiments, we found that PRL ameliorates hepatic steatosis via the hepatic PRLR and fatty acid translocase (FAT)/CD36, a key transporter of free fatty acid uptake in liver. Our findings suggest a novel approach to improving NAFLD using PRL and PRLR. Clinical trial number: NCT03296605.

中文翻译：

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催乳素通过 CD36 途径改善肝脂肪变性

背景与目的 催乳素（PRL）是一种多功能多肽，对代谢有影响，但其对肝脏脂肪变性和脂质代谢的影响知之甚少。在此，我们旨在评估 PRL 在非酒精性脂肪性肝病 (NAFLD) 发展中的作用。方法 对 456 例 NAFLD 患者、403 例经超声诊断为 NAFLD 的非 NAFLD 对照组和 85 例代谢手术肝脏组织学个体（NAFLD 女性 44 例、男性 30 例，年龄匹配的非 NAFLD 女性患者 11 例）的血清 PRL 水平进行分析。评估。在人类肝脏和 HepG2 细胞中评估了编码催乳素受体 (PRLR) 的基因和参与肝脏脂质代谢的信号分子的表达。在游离脂肪酸 (FFA) 处理的 HepG2 细胞中测试了 PRLR 或脂肪酸转位酶 (FAT)/CD36 过表达或 PRLR 敲低对肝脏脂质代谢的影响。结果 超声诊断为 NAFLD 的个体的循环 PRL 水平低于非 NAFLD（男性：7.9 [范围，5.9-10.3] µg/L；女性：8.7 [范围，6.1-12.4] µg/L） ：9.1 [范围，6.8-13.0] µg/L，p = 0.002；女性：11.6 [范围，8.2-16.1] µg/L，p <0.001）。与轻度至中度肝脂肪变性患者相比，活检证实的重度肝脂肪变性患者的 PRL 水平较低（8.3 [范围，5.4-9.5] µg/L vs. 9.7 [范围，7.1-12.3] µg） /L，p = 0.031）和女性（8.5 [范围，4.2-10.6] µg/L vs. 9.8 [范围，8.2-15.7] µg/L，p = 0.027）。此外，NAFLD患者肝脏PRLR基因表达显着降低，与CD36基因表达呈负相关。在 FFA 诱导的 HepG2 细胞中，PRL 处理或 PRLR 过表达显着降低了 CD36 的表达和脂质含量，这些影响在 PRLR 沉默后消失。此外，CD36 的过表达显着降低了 PRL 介导的脂质含量改善。结论 我们的结果揭示了中枢神经系统和肝脏之间的一种新关联，PRL/PRLR 通过 CD36 途径改善了肝脏脂质积累。概述 我们的临床研究表明，催乳素 (PRL)/催乳素受体 (PRLR) 与非酒精性脂肪肝 (NAFLD) 的存在呈负相关。使用细胞实验，我们发现 PRL 通过肝脏 PRLR 和脂肪酸转位酶 (FAT)/CD36（肝脏中游离脂肪酸摄取的关键转运蛋白）改善肝脏脂肪变性。我们的研究结果提出了一种使用 PRL 和 PRLR 改善 NAFLD 的新方法。临床试验编号：NCT03296605。